First-Line Systemic Therapy Outcomes in Western Population with Locally Advanced and Metastatic Gastric Cancer—A Systematic Review

: Globally, gastric cancer is a major cause of cancer mortality, with a 5-year survival rate of 32% for locally advanced and metastatic gastric cancer (A/MCG). This systematic literature review summarized the clinical, safety, and humanistic outcomes associated with systemic regimens administered as a ﬁrst-line therapy for A/MGC. The search included articles published in English in PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and the American Society of Clinical Oncology meeting library, from inception to April 2022. Phase II and III randomized controlled trials (RCTs) conducted among western populations diagnosed with stage III and IV A/MGC were included. Two investigators independently reviewed the studies, conducted data extraction, and assessed risk of bias in accordance with PRISMA guidelines. Twenty-four randomized controlled trials totaling 8705 patients were included. Median overall survival ranged from 5.0 to 13.1 months, median progression-free survival ranged from 2.0 to 7.7 months, and objective response ranged from 13.0 to 64.1%. Two studies reported high quality-of-life outcomes. Grade 3 and 4 adverse events were reported in most studies. This review provides a comprehensive overview of ﬁrst-line systemic therapy outcomes in western populations with A/MGC. With the evolving treatment landscape of A/MGC, an improvement in clinical outcomes can be seen in recently published RCTs with immunotherapies. The potential of new targeted treatments and immunotherapies may present more favorable forthcoming options for treating A/MGC.


Introduction
Gastric cancer is the fifth most diagnosed cancer and the fourth most common cause of cancer-related mortality globally [1].The common risk factors for gastric cancer comprise a combination of environmental and genetic factors.These multifactorial etiologies include Helicobacter pylori infection, smoking, alcohol, high intake of salt and preserved food, and inherited genetic mutations [2].Chronic infection with Helicobacter Pylori can lead to the development of gastritis and its further progression into gastric cancer.This bacterial infection is also classified as a class I carcinogen by the World Health Organization [3], and a strong association between Helicobacter Pylori and gastric cancer has been confirmed in various epidemiological studies [4].CagA is a toxin produced by Helicobacter pylori that can become cancerous and cause uncontrolled cell growth and enhance cell mobility and chronic inflammation of stomach cells [5].Certain genes such a glutathione S-transferase Mu, GSTM1-null phenotype, and Cadherin-1 (CDH1) gene are found to be strongly associated with this carcinoma [6].The germline mutation of CDH1 gene has been found to be associated with a 70% increase in susceptibility to gastric cancer [7].Many environmental factors contribute to gastric cancer development, among which smoking is considered a major factor.There is a dose-response relationship whereby duration and frequency of smoking increases the risk of gastric cancer exponentially [8].Furthermore, dietary factors such as salt and preserved foods are major causes of gastric cancer, while fruits and vegetables exhibit a protective effect [9].Diagnosis of stomach cancer in the initial stages of the disease is usually rare since around 80% of the patients are asymptomatic in this phase [10].Currently, there are no screening guidelines for gastric cancer in the United States.In patients with associated symptoms like abdominal pain, vomiting, and nausea, initial workup for stomach cancer along with medical history is conducted.The most common diagnostic modalities for stomach cancer are upper endoscopy and computed tomography (CT) scan [11].
There are an estimated 26,560 cases of gastric cancer in the United States (US) alone, and 11,180 deaths were recorded in 2021.In the US, 1.5% of new cancers diagnosed per year are attributed to gastric cancer [12].Studies have shown that 65% of gastric cancer cases diagnosed in the US are at an advanced stage (tumor node metastasis stages T3 or T4) [2].Locally A/MGC has a poor prognosis with a survival rate of only 5-10% [2].
In cases of locally A/MGC, systemic therapy is often the preferred treatment since it offers survival benefits [13].Patients with advanced disease are usually treated with a combination chemotherapy that has become the accepted standard for first-line treatment [14].According to recommendations from the National Comprehensive Cancer Network [14], a fluoropyrimidine (fluorouracil), a platinum-based antineoplastic agent (oxaliplatin or cisplatin), and a taxane (docetaxel or paclitaxel) can be added to therapy.The National Comprehensive Cancer Network also recommends patients with metastatic gastric cancer to consider undergoing testing for human epidermal growth factor receptor 2 (HER2) amplification and presence of programmed death-ligand 1 (PD-L1) [14].In HER2-positive patients, trastuzumab is recommended as a first-line therapy [15].Immune checkpoint inhibitors are a recent class of drugs that act by inhibiting T-cell activation and effector functions, leading to an anti-tumor response [16].Specifically, immune checkpoint inhibitors in locally advanced and metastatic gastric cancer patients act by mediating the blockage of the programmed cell death protein 1 (PD-1)/PD-L1 axis.They are preferred in standard chemotherapy refractory cases or for patients who have been previously treated with two or more chemotherapeutic regimens [17].
Immune activation by immune checkpoint inhibitors seems to have a more durable clinical benefit than traditional chemotherapy in locally A/MGC and a lower incidence of adverse events [18,19].The ATTRACTION-2 phase III clinical trials l assessed Nivolumab or placebo in metastatic gastric cancer patients and showed significant overall survival that persisted over time [20].Immune checkpoint inhibitor combinations can also lead to higher toxicities, but no increase in their activity was observed as noted in the MOONLIGHT trial, which was conducted with Nivolumab in locally A/MGC patients [21].Long-term side effects have also been a cause of concern with immune checkpoint inhibitors.A real-world study assessing melanoma patients treated with immune checkpoint inhibitors found that 40% of patients exhibited immune-related adverse events at follow-up [22].
The clinical efficacies of several targeted agents and immunotherapy treatment options have been tested in phase II and phase III randomized clinical trials.However, there is still ambiguity regarding the drug of choice for locally A/MGC patients.Previously published systematic reviews evaluated first-line systematic therapies in locally A/MGC, but each had some important limitations [23][24][25][26], such as are outdated, do not include all systemic therapies, or included both gastric and esophageal cancer patients.
There is a lack of established screening programs in the western world, making the early detection of gastric cancer difficult and resulting in poor survival rate in locally A/MGC.The literature shows that treatment efficacy and survival outcomes vary between Asian and Western patients.There is a lack of comprehensive, current evidence regarding therapies approved by the US Food and Drug Administration for locally A/MGC.Hence, the purpose of this study was to perform a systematic review of randomized phase II and phase III treatment trials to compare the clinical efficacy, safety (adverse events), and humanistic outcomes of all first-line systemic therapeutic combinations among the western adult population with locally A/MGC.

Types of Studies
Phase II and phase III RCTs were included in the systematic review if they compared a systemic first-line single agent or combination therapy, as per the National Comprehensive Cancer Network guidelines (version 2.2022), [14] with another type of systemic first-line therapy, placebo, best supportive care, or no treatment as comparison groups.We included the full text or the abstract of studies if data for outcomes were reported.We included trials with mixed disease stages if they reported outcomes separately for metastatic disease.

Types of Participants
Adults aged 18 years and older with histologically confirmed adenocarcinoma of the stomach and locally advanced unresectable or metastatic disease were included.Trials and studies of patients with adjacent organs and lymph node metastasis (defined as American Joint Committee on Cancer tumor node metastasis stage III) and distant metastatic (defined as American Joint Committee on Cancer tumor node metastasis stage IV) gastric cancer were included.No restrictions in terms of sex, drug dosage, radiologic examination, or treatment duration were applied.

Types of Interventions
All comparisons of systemic therapies for the treatment of locally advanced and metastatic gastric cancer as per National Comprehensive Cancer Network guidelines 2022 [14] were included, such as immune checkpoint inhibitors; single-agent chemotherapy; double/triple agent chemotherapy; and targeted drug therapy.

Types of Outcome Measures
All relevant outcomes available in the reports were included, such as overall survival (defined as survival time from the start of the intervention until death from any cause); progression-free survival (defined as survival time without disease progression or death from the start of the intervention, i.e., randomization); time to progression (defined as time from randomization in the study to tumor progression); objective response rate (defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors); quality of life (measured using a validated scale/questionnaire); and grade 3 or higher serious adverse events (measured using National Cancer Institute-Common Terminology Criteria for Adverse Events) [27].

Search Strategy
The literature search was conducted to identify all published and unpublished phase II and phase III randomized controlled trials.Four electronic databases (PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) were thoroughly searched as were the abstracts from the American Society of Clinical Oncology (ASCO) meeting library.Reference lists of primary studies were reviewed, and included articles were checked for any further references.Google and Google Scholar were also searched to identify any missing trials.
The search strategy was built with the help of a health sciences librarian, and it consisted of a combination of Medical Subject Heading (MeSH) terms and text words related to gastric cancer, metastases, and first-line systemic therapies.The MEDLINE search strategy (Table 1) was developed first, and then adapted for use in the other databases (Appendix A).The search was confined to English language publications and trials conducted among western populations, and it was conducted from database inception until April 2022.Trials with the longest follow-up periods were selected if multiple reports existed for the same trial.

Selection Criteria
Studies were included if they described phase II or phase III RCTs, included metastatic gastric cancer patients with tumor node metastasis phase III or phase IV, included patients who received at least one anti-tumor systemic therapy as recommended by National Comprehensive Cancer Network guidelines 2022, or described both gastric and esophageal cancer cases where subgroup data on gastric cancer were available.
Studies were excluded if they were non-randomized controlled trial designs or preclinical experiments, observational studies, case reports, duplicate publications, commentaries or editorials, pooled analyses, clinical trials without comparisons, published in languages other than English, included trial participants from outside western populations, described therapies other than first-line systemic therapy, or described only palliative care trials.
Two reviewers (S.M. and D.A.) independently screened all titles and abstracts identified using the search methods described.The full texts of all possibly relevant studies were retrieved and assessed for eligibility.Any discordance was resolved by consensus and with the help of a third reviewer (T.W) where necessary.A data screening tool that was specifically designed for this purpose was used.Ineligible studies with reasons for exclusion were identified and recorded.The selection process was recorded in sufficient detail to complete a PRISMA flow diagram (Figure 1).fied using the search methods described.The full texts of all possibly relevant studies were retrieved and assessed for eligibility.Any discordance was resolved by consensus and with the help of a third reviewer (T.W) where necessary.A data screening tool that was specifically designed for this purpose was used.Ineligible studies with reasons for exclusion were identified and recorded.The selection process was recorded in sufficient detail to complete a PRISMA flow diagram (Figure 1).

Data Extraction and Management
A standard data collection form was designed for this study and included details on the study characteristics and outcomes.Two independent reviewers (S.M and D.A)

Data Extraction and Management
A standard data collection form was designed for this study and included details on the study characteristics and outcomes.Two independent reviewers (S.M and D.A) extracted study characteristics and outcome data from included studies and met to achieve consensus.

Risk of Bias Assessment
Two independent authors (SM and DA) assessed the included studies in accordance with version two of the Cochrane risk-of-bias tool for randomized trials [28].The two reviewers compared their evaluations and resolved any possible discrepancies with a third reviewer who is a content expert (T.W).Overall risk of bias for each study included was reported in accordance with the risk-of-bias tool as low risk of bias, some concerns, or high risk of bias.

Data Synthesis
Endnote was used to organize studies from different databases and to remove duplicate studies.A table summarizing the included studies was created using the captured study characteristics and outcomes.The design, conduct, and writing of this systematic review was in accordance with the PRISMA Checklist.

Characteristics of Included Studies
A total of 8689 unique references were identified from the database search, and after reviewing titles and abstracts, 8510 were excluded.In the remaining 179 full-text articles, 24 studies met the inclusion criteria and were included in our systematic review.The selection process and reason for exclusion are reported in the PRISMA flow diagram (Figure 1).These 24 studies included eight phase II RCTs and 16 phase III RCTs.
Of the 24 included trials, 21 contained two treatment arms while the remaining three contained three treatment arms.Double chemotherapy combinations were used as firstline therapy in five RCTs, while the remaining 19 trials used triple or quadruple drug combination therapies.The total number of included patients per study ranged from 69 to 1581.The median participant ages ranged from 52.7 to 70 years, and 48% to 84% of participants were male.The characteristics of the included RCTs and demographic characteristics of study participants are shown in Table 2.
The characteristics of the cancer and outcomes reported are presented in Table 3.More than 50% of trial patients had a gastric tumor.The proportion of trial participants with metastatic disease was between 60% and 97.3%.

Overall Survival
Of the 24 included trials , 21 reported overall survival with 39 different treatment regimens.Only 4 of the 20 trials reporting overall survival identified a statistically significant difference between the intervention and comparison groups.One of the four studies that showed statistically significant differences in overall survival was Cascinu, 2011 [35], that evaluated a three-drug combination of pegylated liposomal doxorubicin, 5-fluouracil, and cisplatin with mitomycin-C, 5-fluouracil, and cisplatin as the comparative arm and found that the doxorubicin, 5-fluouracil, and cisplatin group had a higher overall survival (12.1 months vs. 8.3 months).The second of the four studies was Catenacci, 2017 [36].This was a phase III RCT that compared a four-drug combination of rilotumumab plus standard of care (standard of care consisted of epirubicin, cisplatin, and capecitabine) compared to standard of care alone.The rilotumumab-standard of care group showed poorer outcomes in overall survival (8.8 months) compared to the standard of care group (10.7 months).The third of the four studies was Janjigian, 2021 [44].This study was conducted among locally A/MGC patients where nivolumab therapy with chemotherapy was compared to chemotherapy alone.The nivolumab group showed significantly higher overall survival (13.1 months vs. 11.1 months) than the chemotherapy alone group.
The fourth study was Van Cutsem, 2006 [51].This study compared docetaxel, cisplatin, and fluorouracil with cisplatin-fluorouracil and found a longer overall survival of 9.2 months in the docetaxel, cisplatin, and fluorouracil group compared to 8.6 months in the cisplatin-fluorouracil group among advanced gastric cancer patients.Among the remaining included studies that reported overall survival, 16 randomized controlled trials used various treatment regimens, and 12 of which did not show statistical differences in overall survival between the treatment and comparator groups, while the remaining four RCTs did not report statistical results (Table 4).

Progression-Free Survival
A total of 13 of the 24 included RCTs using 39 regimens reported progression-free survival outcomes.Only 6 of the 13 RCTs showed statistically significant improvements in progressionfree survival.The first study reporting progression-free survival by Catenacci, 2017 [36], was a phase III trial among advanced gastric cancer patients with rilotumumab plus standard of care (standard of care consisted of epirubicin, cisplatin, and capecitabine) compared to standard of care alone.This study showed that rilotumumab plus standard of care had a shorter progressionfree survival (5.6 months) compared to standard of care alone (6.07 months).The second study reporting progression-free survival by Fuchs, 2019 [40] was a phase III trial comparing ramucirumab and standard first-line therapy (fluorouracil and capecitabine) with placebo plus standard first-line therapy.Ramucirumab plus first-line therapy showed a significantly longer progression-free survival (5.7 months) compared to placebo and first-line therapy (5.4 months).The third study reporting progression-free survival by Janjigian, 2021 [44], was a phase III RCT that compared the role of the newer agent nivolumab and standard chemotherapy with standard chemotherapy alone.Nivolumab and standard chemotherapy showed longer progression-free survival (7.7 months) compared to the chemotherapy alone group (6.1 months).The fourth study reporting progression-free survival by Kang, 2009 [45], was a randomized phase III noninferiority trial that compared capecitabine/cisplatin to 5-fluorouracil/cisplatin.The capecitabine/cisplatin group showed significant noninferiority for progression-free survival in patients with advanced gastric cancer of 5.6 months versus 5.0 months for the 5-fluorouracil/cisplatin group.The fifth study reporting progression-free survival conducted by Shitara, 2020 [49], was a phase III trial comparing three groups (group 1: pembrolizumab alone, group 2: standard chemotherapy, and group 3: pembrolizumab and standard chemotherapy).Progression-free survival was higher in group 2 (standard chemotherapy) when compared to group 1 (pembrolizumab alone) with 6.4 months and 2.0 months progression-free survival, respectively.The sixth study reporting progression-free survival conducted by Shitara, 2022 [50] compared nivolumab plus ipilimumab to chemotherapy alone (i.e., the CheckMate 649 trial).Chemotherapy alone showed a longer progression-free survival (7.1 months) than nivolumab plus ipilimumab (2.8 months) (Table 4).S1 is a novel oral fluoropyrimidine derivative.NR = not reported in the study.CI = confidence interval.HR = hazards ratio.Hazards ratio and p values in bold indicates statistically significant values of p < 0.05.

Other Outcomes Reported
Some of the other statistically significant clinical efficacy outcomes reported in the included clinical trials were time to 5% deterioration of global health status from baseline (a quality-of-life assessment), mean difference in global health scores (also a quality-of-life measure), and time to progression.Anjani, 2007 [30], prospectively assessed quality of life as one of the secondary end points of the phase III trial that compared docetaxel-cisplatinfluorouracil with cisplatin-fluorouracil.Time to 5% deterioration of global health status from baseline was longer in the docetaxel-cisplatin-fluorouracil group, i.e., 6.5 months, compared to 4.2 months in the cisplatin-fluorouracil group, showing the better maintenance of quality of life with the addition of docetaxel.All three treatments arms in the Bouche, 2004 [34], trial exhibited improved global quality-of-life health scores when compared to baseline.Time to progression showed statistically significant improvements in two studies: Cascinu, 2011 [35] and Van Cutsem, 2006 [51] (Table 4).

Adverse Events and Safety
A total of 22 of the 24 included RCTs reported some grade of adverse events in study patients.Only grade 3 and higher treatment-related adverse events are summarized in Table 4.The most common grade 3-4 hematological toxicities were neutropenia, anemia, thrombocytopenia, and leucopenia, while the most common nonhematological toxicities were nausea, vomiting, diarrhea, and fatigue (Table 5).

Risk of Bias Assessment
Of the 24 included studies, 11 studies had a low overall risk of bias, and 13 studies had some concerns overall.None of the eligible studies were at high risk of bias as rated by the five domains of the risk-of-bias tool [28] (Table 6).Low = low risk of bias, Some = some concerns in risk of bias.

Discussion
First-line treatment recommendations for patients with locally A/MGC have been constantly updated in the US.The National Comprehensive Cancer Network Gastric Cancer Guidelines (Version 2.2022) recommends a fluoropyrimidine (fluorouracil or capecitabine), a platinum-based antineoplastic (oxaliplatin or cisplatin), and trastuzumab (for HER2 overexpression positive adenocarcinoma) or nivolumab (for HER2 overexpression negative adenocarcinoma) as preferred first-line systemic therapy for unresectable, recurrent, or metastatic gastric cancer [14].This systematic review identified numerous first-line therapeutic options investigated in 24 RCTs among patients with locally A/MGC before April 2022.Across treatment arms in the included RCTs, median overall survival was between 5.0 months and 13.1 months, median progression-free survival was between 2.0 months and 7.7 months, and the objective response rate was between 13.0% and 64.1%.The wide range of values across these outcomes highlighted some inconsistencies across the included studies.Multiple factors likely contributed to this cross-study variability such as differences in trial phases, treatment arms, sample sizes, disease stages included, and the Eastern Cooperative Oncology Group (ECOG) status of the included patients.Specific examples of the outcomes studied are reported and discussed in the context of what is already known in the following sections.

Overall Survival
The combination of nivolumab plus chemotherapy seems to produce the longest overall survival (hazard ratio = 0.71, 95% confidence interval [CI] = 0.59-0.86),while the shortest overall survival length was observed with the 5-fluorouracil-epirubicin-cisplatin combination.Reasons that can explain this finding are not well documented; nevertheless, it is an encouraging finding.Immune checkpoint inhibitors have durable and significantly higher clinical efficacy than chemotherapy alone in locally A/MGC patients.In accordance with the above outcomes, the combination of nivolumab and fluoropyrimidine with platinumbased antineoplastics is the recommended treatment for locally A/MGC [14] due to its better overall survival outcomes.Compared with the prior systematic review conducted by Cheng and colleagues in 2018 [53] that included studies that contained both gastric and esophageal cancer cases and included worldwide trial populations, our systematic review focused on studies that included only western populations with gastric cancer [53].Cheng et al. found that fluoropyrimidine plus platinum-based triple therapies (hazard ratio = 0.91, 95% CI = 0.83-0.99)showed the highest improvement in overall survival in patients with advanced gastric cancer.An older systematic review by Wagner, 2006 [54], assessed first-line chemotherapy in patients with advanced gastric cancer and included overall survival as the primary outcome.This study also showed a three-drug regimen of fluorouracil, cisplatin, and an anthracycline (doxorubicin or epirubicin) achieved better survival results (hazard ratio = 0.77, 95% CI = 0.62-0.91)than a two drug (fluorouracilcisplatin) combination.With the recent advancements in immunotherapies, nivolumab (a PD-L1 inhibitor) has demonstrated a significant survival benefit in the locally advanced and metastatic gastric cancer population, and our review supports these results [55].

Progression-Free Survival
Similar to the overall survival results, a combination of nivolumab and chemotherapy showed the longest progression-free survival duration of 7.7 months (hazard ratio = 0.68, 95% CI = 0.56-0.81)among our included RCTs.In support of our findings, the CheckMate-649 trial results indicated that nivolumab was the first PD-L1 inhibitor to demonstrate superior progression-free survival duration of 7.7 months (hazard ratio = 0.68, 95% CI = 0.56-0.81)among advanced gastric cancer patients [55].CheckMate-649 is the largest randomized, global phase III study of an immune checkpoint inhibitor-based therapy as first-line therapy for patients with gastric and esophageal cancers conducted to date.While our systemic review found that nivolumab plus chemotherapy showed the longest progression-free survival, in contrast to our findings, an older systematic review and network meta-analysis by Cheng and colleagues in 2018 [53] found that fluoropyrimidine-platinum-based triple-medication therapy (hazard ratio = 0.75, 95% CI = 0.54-1.04)was the best regimen for progression-free survival.However, at the time Cheng et al. was conducted, nivolumab was still under development and therefore was not included.Another review article by Takashima, 2017, investigated survival outcomes in advanced gastric cancer in phase III trials.Median progression-free survival was calculated from 11 trials from all over the world and found to be in the range of 3.1 to 7.4 months [56].The phase III trials included in this review did not include newer studies utilizing immunotherapies like nivolumab because the search was conducted from 2007 to 2015.

Objective Response Rate
In this review, the highest objective response rate was found in the Cascinu, 2011 [35], study with a rate of 64.1% in the doxorubicin-5-fluorouracil-cisplatin group.An American Society of Clinical Oncology post on the long-term support data of the CheckMate-649 trial of nivolumab plus chemotherapy group reported that with longer follow-up, the nivolumab-chemotherapy group had a higher objective response rate (58%) than chemotherapy alone [55].As per the older systematic review by Cheng and colleagues, 5-fluorouracil plus platinum doublet (oxaliplatin or cisplatin) demonstrated statistically significant results among the 89 global studies investigated.Another older review by Koizumi, 2007 [57], assessed the global status of chemotherapies for advanced gastric cancer and concluded that a promising objective response rate did not always translate into a survival benefit.

Other Outcomes
Our review showed that the mean global health status showed significant improvement compared to the baseline in two different studies.Interim results of nivolumabchemotherapy versus chemotherapy from the CheckMate-649 trial showed that a change from baseline in health-related quality of life as assessed by EuroQol-5-dimension (EQ-5D) scores favored nivolumab-chemotherapy [58].A systematic review by van Amelsfoort, in 2021, evaluated health-related quality of life among patients with non-metastatic locally advanced gastric cancer.This review found that health-related quality of life deteriorated during the first three months after surgery and chemoradiotherapy [59].

Limitations
This review possesses a few limitations.Oncology is a very complex and rapidly evolving area; thus, there is a significant heterogeneity observed in treatment arms and outcomes.Next, only systemic therapies are summarized in this review; thus, surgical interventions and radiation therapy that are cardinal in the treatment of gastric cancer have not been included.Also, our study included only RCTs conducted in western populations, and thus, the obtained results cannot be extrapolated to draw global conclusions.Clinical efficacy and safety outcomes observed in observational studies and real-world studies were also beyond the scope of this systematic review, and thus, our results do not necessarily reflect subsequent changes in clinical practice.In addition, a publication bias can be a concern for any systematic review as studies that did not identify the treatment to be effective may not have been published.To minimize publication bias, our literature search also included any unpublished or ongoing trials.With a variety of novel immune check point inhibitors and targeted therapies that are being explored in the oncology space, some of the ongoing trials have not yet published their comprehensive results.

Future Research
With emerging clinical data for checkpoint inhibitors in locally A/MGC, immunotherapies such as nivolumab have the potential to improve outcomes in patients who have unresectable, locally A/MGC, and they may provide new treatment options for this patient population in the future.Identification of predictive biomarkers for gastric cancer is being conducted on a larger scale [60].Examples of these biomarkers include tumor agnostic biomarker, mismatch repair, or microsatellite instability, which is a robust biomarker of immune responses.Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who may benefit from immunotherapy or targeted therapy [61].New initiatives in gastric cancer research focus on the identification of new potential molecular targets through genetic profiling of the disease using molecular diagnostic techniques.Extensive translational research, diagnostic investigations, and multi-omics-based clinical trials will lead to breakthroughs in the diagnosis and treatment of gastric cancer [62].Future research should aim to supplement the published data by conducting larger real-world observational studies, considering the widespread testing of biomarkers for locally advanced and metastatic gastric cancer, and also seeking to evaluate the economic and quality-of-life burdens of locally advanced and metastatic gastric cancer.

Conclusions
With the evolving treatment landscape, an improvement in clinical and safety outcomes can be observed in recently published randomized controlled trials.The potential of new targeted treatments and immunotherapies may present more favorable forthcoming options for locally advanced and metastatic gastric cancer.

Table 1 .
PubMed Search Strategy.

Table 2 .
Baseline characteristics of included randomized control trials of untreated locally advanced and metastatic gastric cancer.
NR = not reported in the study.S-1 is a novel oral fluoropyrimidine derivative.+ = min-max.* = mean and standard deviation.

Table 3 .
Characteristics of the cancer and reported outcomes.
NR = not reported in the study.ECOG = Eastern Cooperative Oncology Group.

Table 4 .
Efficacy of the first-line systemic treatments among trial patients with locally advanced and metastatic gastric cancer.

Table 5 .
Grade three or four adverse events and outcomes reported in included studies.

Table 6 .
Risk of bias summary of all included randomized control trials using the Cochrane Risk of Bias tool.